10-5960405-T-G

Position:

• chr10-5960405-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002189.4(IL15RA):​c.545A>C​(p.Asn182Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,613,568 control chromosomes in the GnomAD database, including 208,485 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.55 (23846 hom., cov: 30)
  • Exomes 𝑓: 0.50 (184639 hom.)
• Consequence: IL15RA NM_002189.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.137

Genes affected

IL15RA (HGNC:5978): (interleukin 15 receptor subunit alpha) This gene encodes a cytokine receptor that specifically binds interleukin 15 (IL15) with high affinity. The receptors of IL15 and IL2 share two subunits, IL2R beta and IL2R gamma. This forms the basis of many overlapping biological activities of IL15 and IL2. The protein encoded by this gene is structurally related to IL2R alpha, an additional IL2-specific alpha subunit necessary for high affinity IL2 binding. Unlike IL2RA, IL15RA is capable of binding IL15 with high affinity independent of other subunits, which suggests distinct roles between IL15 and IL2. This receptor is reported to enhance cell proliferation and expression of apoptosis inhibitor BCL2L1/BCL2-XL and BCL2. Multiple alternatively spliced transcript variants of this gene have been reported.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.351063E-6).
• BP6: Variant 10-5960405-T-G is Benign according to our data. Variant chr10-5960405-T-G is described in ClinVar as [Benign]. Clinvar id is 1232028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL15RA	NM_002189.4	c.545A>C	p.Asn182Thr	missense_variant	4/7	ENST00000379977.8	NP_002180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL15RA	ENST00000379977.8	c.545A>C	p.Asn182Thr	missense_variant	4/7	1	NM_002189.4	ENSP00000369312.3

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83149 AN: 151734 Hom.: 23812 Cov.: 30

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.523

GnomAD3 exomes AF: 0.507 AC: 127468 AN: 251432 Hom.: 33053 AF XY: 0.503 AC XY: 68294 AN XY: 135896

Gnomad AFR exome AF: 0.723

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.522

Gnomad EAS exome AF: 0.422

Gnomad SAS exome AF: 0.536

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.485

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.500 AC: 731339 AN: 1461716 Hom.: 184639 Cov.: 50 AF XY: 0.500 AC XY: 363600 AN XY: 727166

Gnomad4 AFR exome AF: 0.718

Gnomad4 AMR exome AF: 0.531

Gnomad4 ASJ exome AF: 0.530

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.493

Gnomad4 OTH exome AF: 0.508

GnomAD4 genome AF: 0.548 AC: 83242 AN: 151852 Hom.: 23846 Cov.: 30 AF XY: 0.544 AC XY: 40381 AN XY: 74220

Gnomad4 AFR AF: 0.709

Gnomad4 AMR AF: 0.519

Gnomad4 ASJ AF: 0.535

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.523

Alfa AF: 0.495 Hom.: 46845

Bravo AF: 0.561

TwinsUK AF: 0.489 AC: 1812

ALSPAC AF: 0.483 AC: 1861

ESP6500AA AF: 0.719 AC: 3167

ESP6500EA AF: 0.489 AC: 4202

ExAC AF: 0.512 AC: 62156

Asia WGS AF: 0.494 AC: 1720 AN: 3478

EpiCase AF: 0.483

EpiControl AF: 0.477

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 21085059) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.39
DANN	Benign	0.41
DEOGEN2	Benign	0.0026	.;T;T;.;.;.;.;.;T;.;.;T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.049	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0000014	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	.;.;N;.;.;.;.;.;.;.;N;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.55	.;.;N;.;.;N;N;N;.;N;N;.;.;N;N
REVEL	Benign	0.060
Sift	Benign	1.0	.;.;T;.;.;T;T;T;.;T;T;.;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;.;T
Polyphen		0.0	.;.;B;.;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.062
MPC		0.11
ClinPred		0.0091	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.073

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2228059; hg19: chr10-6002368; COSMIC: COSV66092735;